Recently, resistance to anthelmintics has emerged as the most important problem confronting the control of parasitic nematodes of ruminants. Resistance in parasites of other economically significant animals has also been reported and there can be little doubt that the incidence of resistance will increase and eventually also appear in medically important parasites of man. The impact of resistance has been contained by the introduction of ivermectin, the most potent and arguably the most efficacious anthelmintic ever developed. However, recent reports suggest that development of resistance may soon reduce its value. Extensive investigations of ivermectin resistance in the model nematode Caenorhabditis elegans have generated a specific hypothesis regarding the likely form of ivermectin resistance in parasitic nematodes. The goals of the proposed Phase I research are to test the hypothesis and to identify the genes responsible for ivermectin resistance in parasitic nematodes. During Phase II these genes will be cloned and diagnostic reagents capable of detecting ivermectin resistance in parasites will be developed. Diagnostic reagents will provide early warning of emerging resistance and an ability to monitor the efficacy of new methods designed to limit, and preferably reverse, the growth of ivermectin resistant populations (Phase III).